Genetic variability in HIV-1 gp120 affects interactions with HLA molecules and T cell receptor

The propensity of HIV-1 to undergo sequence variation, particularly in the envelope glycoprotein gp120, complicates vaccine development and may enable the virus to evade ongoing immune responses in infected individuals. We present here a molecular analysis of the effects of this variability on human T cell recognition of HIV-1 gp120. Synthetic peptides representing a defined CD4+ human T cell epitope in gp120 were used to survey gp120 molecules from various HIV-1 strains for the capacity to be recognized in the context of a single human MHC molecule, DR4. Variation affected recognition at two levels. For some strains, variation in this epitope was sufficient to alter the interaction of Ag receptors on gp120-specific human T cell clones with peptide-DR4 complexes on APC. In the case of two strains, the natural variation was sufficient to prevent the critical initial interaction between the relevant gp120 peptides and DR4 on the APC. However, these strains were highly divergent from the reference strain. Thus it is encouraging to note that the range of natural sequence variation in this T cell epitope falls, for the most part, within the range of peptide sequences that can be accommodated by the relevant human MHC molecule.     

Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family.

We have isolated and sequenced a full-length cDNA clone encoding rat glyceraldehyde-3-phosphate-dehydrogenase (GAPDH, E.C.1.2.1.12). The entire mRNA is 1269 nucleotides long exclusive of poly(A) and contains respectively 71 and 196 bases of 5' and 3' non-coding regions. Primer extension as well as S1 nuclease protection experiments clearly established that a single (or at least a highly prominent) GAPDH mRNA species is expressed in all rat tissues examined. This sequence allowed the determination of the hitherto unknown primary structure of rat GAPDH which is 333 aminoacids long. Comparison between GAPDH sequences from rat, man and chicken revealed a high degree of sequence conservation at both nucleotide and protein levels.     

Abundance and generalisation in mutualistic networks: solving the chicken‐and‐egg dilemma

A frequent observation in plant–animal mutualistic networks is that abundant species tend to be more generalised, interacting with a broader range of interaction partners than rare species. Uncovering the causal relationship between abundance and generalisation has been hindered by a chicken‐and‐egg dilemma: is generalisation a by‐product of being abundant, or does high abundance result from generalisation? Here, we analyse a database of plant–pollinator and plant–seed disperser networks, and provide strong evidence that the causal link between abundance and generalisation is uni‐directional. Specifically, species appear to be generalists because they are more abundant, but the converse, that is that species become more abundant because they are generalists, is not supported by our analysis. Furthermore, null model analyses suggest that abundant species interact with many other species simply because they are more likely to encounter potential interaction partners.     

Improved Pancreatic Adenocarcinoma Diagnosis in Jaundiced and Non-Jaundiced Pancreatic Adenocarcinoma Patients through the Combination of Routine Clinical Markers Associated to Pancreatic Adenocarcinoma Pathophysiology

Background

There is still no reliable biomarker for the diagnosis of pancreatic adenocarcinoma. Carbohydrate antigen 19–9 (CA 19–9) is a tumor marker only recommended for pancreatic adenocarcinoma follow-up. One of the clinical problems lies in distinguishing between this cancer and other benign pancreatic diseases such as chronic pancreatitis. In this study we will assess the value of panels of serum molecules related to pancreatic cancer physiopathology to determine whether alone or in combination could help to discriminate between these two pathologies.

Methods

CA 19–9, carcinoembryonic antigen (CEA), C-reactive protein, albumin, insulin growth factor-1 (IGF-1) and IGF binding protein-3 were measured using routine clinical analyzers in a cohort of 47 pancreatic adenocarcinoma, 20 chronic pancreatitis and 15 healthy controls.

Results

The combination of CA 19–9, IGF-1 and albumin resulted in a combined area under the curve (AUC) of 0.959 with 93.6% sensitivity and 95% specificity, much higher than CA 19–9 alone. An algorithm was defined to classify the patients as chronic pancreatitis or pancreatic cancer with the above specificity and sensitivity. In an independent validation group of 20 pancreatic adenocarcinoma and 13 chronic pancreatitis patients, the combination of the four molecules classified correctly all pancreatic adenocarcinoma and 12 out of 13 chronic pancreatitis patients.

Conclusions

Although this panel of markers should be validated in larger cohorts, the high sensitivity and specificity values and the convenience to measure these parameters in clinical laboratories shows great promise for improving pancreatic adenocarcinoma diagnosis.     

Identification of developmental toxicants using the Frog Embryo Teratogenesis Assay-Xenopus (FETAX)

Because growth and development are processes sensitive to the action of many chemicals, bioassays that screen for developmental toxicants may be more indicative of chronic effects than acute toxicity assays. FETAX is a 96 h whole embryo static renewal test employing the embryos of the frog Xenopus laevis. Endpoints are mortality, malformation and growth. Because of the frog's fecundity, its extensive use in basic research and the ability to obtain embryos year-round, it is an ideal organism to use in screening for developmental toxicants. By validating using known mammalian teratogens and the use of rat liver microsomes to stimulate mammalian metabolism, we have extended the use of the system for the prescreening of human developmental toxicants. In past validation work, we have correctly identified the teratogenicity of 15 to 17 compounds used in validation for a predictive accuracy of approximately 88%. In the present study, the ability of FETAX to detect developmental toxicants in groundwater samples taken from an industrial waste dump was evaluated. FETAX showed that it was sensitive enough to detect developmental toxicants in samples without prior concentration. In some samples, less than half the LC50 concentration was required to cause significant malformation. In some cases, a dose-response curve was not obtainable but the test results nonetheless indicated some developmental toxicity. The results of this study indicate that it is necessary to routinely screen for developmental toxicants when establishing water quality criteria for the preservation of species and for human health.     

Targeting viral infection by microRNA inhibition

An inhibitor of microRNA-122 reduces viral load in chimpanzees that are chronically infected with hepatitis C virus, suggesting that such an approach might have therapeutic potential in humans.